Beta-blockers are used for the treatment of high blood pressure, control of angina, arrhythmia, post myocardial infection, heart failure, migraine or essential tremor.
Nebivolol is a highly selective beta-1 blocker and has been found to be useful for the management of hypertension. Hypertension (high blood pressure) is a significant health risk affecting more than 500 million people across the world and needs long-term therapy for its management.
Chemically nebivolol is 2,2′-iminobisethanol derivative i.e., 2H-1-benzopyran-2-methanol, ∝,∝′-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-, [2R*[R*[R*(S*)]]]]. EP 744 946 B1 discloses nebivolol to be a mixture of equal amounts of 2 enantiomers having respectively the SRRR- and the RSSS-configuration.
Methods for preparation of nebivolol are disclosed in EP-0145067 and EP-0334429. EP 0145067 B1 describes a process for the conversion of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (VI) into isomeric mixtures of 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (VII). This reaction entails the use of sodium hydride as the base, which is extremely hazardous. Further, purity of the product, i.e., 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (VII) obtained by using sodium hydride is low and is found to be around 62-65%, which is unacceptable. The mixture of oxiranes represented by the formula (VII) are separated by column chromatography as shown in Scheme (I) to obtain A-isomer of (VII) (i.e., VII-A) from the first fraction and B-isomer of (VII) (i.e., VII-B) from the second fraction.

The A-isomer of (VII) is then treated with benzylamine to obtain the benzylated A-isomer of (VII) (i.e., Intermediate I), which is reacted with the B-isomer in presence of oxalic acid to obtain the oxalate salt of benzylated nebivolol (VIII-a), as shown in Scheme-II.
Furthermore, the oxalate salt (VIII-a) as obtained has to be treated with an alkali to obtain the free benzylated nebivolol base (VIII).

Thus, as can be seen from Scheme II, the reaction between Intermediate-I and (VII-B) involves purification by column chromatography, and subsequent treatment with oxalic acid to form the oxalate salt. Treatment with oxalic acid results in the separation of the undesired (RSRR+SRSS) diastereomers from the desired (RSSS+SRRR) isomers, due to a difference in solubilities between the desired and the undesired isomers. Further, the oxalic acid salt has to be converted to the free benzylated nebivolol base by treatment with an alkali. The multiple steps in the process make it cumbersome and lead to increase in utilities and in the manufacturing time cycle of the active pharmaceutical ingredient. Moreover the purity of the free benzylated nebivolol base is also found to be relatively low.
EP 334429 B1 discloses a process for the preparation of specifically the RSSS isomer of nebivolol independently. The said process for the independent preparation of RSSS nebivolol involves the use of hazardous reagents like thionyl chloride, sodium hydride and di-isobutyl aluminium hydride (DIBAL), expensive optically active reagents like (+)-1,2,3,4,4a,9,10,10a-octahydro-1,4-a-dimethyl-7-(1-methylethyl-1-phenathrenemethanamine[(+)-dehydroabiethylamine] and utilities like column chromatography and low temperatures. The processes also involve a large number of steps thereby increasing in utilities, manpower and time required to complete the production cycle, rendering the process commercially expensive.
Furthermore, EP 744946B1 describes a process for obtaining nebivolol hydrochloride from a mixture containing the desired (RSSS+SRRR) nebivolol base contaminated by the undesired (RSRR+SRSS) diastereomers, using ethanol as both the reaction as well, as the recrystallization solvent. The major disadvantage of the said process is that it uses impure nebivolol base as the starting material containing different isomeric impurities, and thereby results in a very low yield (6.6%) of the desired isomers (having the SRRR- and the RSSS-configuration) of nebivolol hydrochloride. Moreover, ethanol is a solvent that can be used only in controlled quantities due to stringent regulatory requirements, and therefore its use on an industrial scale is limited.
Thus, there exists a need for developing a method for the synthesis of the desired diastereomeric mixture of higher purity with the reduction of undesirable isomeric impurities and eliminating the use of hazardous sodium hydride, while at the same time reducing the process steps in the synthesis of nebivolol.
It has been surprisingly found that the process of synthesizing nebivolol in accordance with the process of the present invention not only increases the purity of the desired diastereomeric mixture in a minimum number of process steps but also eliminates the use of hazardous chemicals in the process.
Nebivolol is mainly used for the treatment and prevention of coronary vascular disorders. It is taken once or twice a day as per the requirement of the patient.
EP 0744946 discloses pharmaceutical compositions of nebivolol where the drug is in micronized form and with the addition of one or more wetting agents specifically polysorbates as an adjuvant. This patent emphasizes the need of micronization and further wetting as the oral administration of nebivolol hydrochloride is impeded by the poor dissolution when in a normal crystalline form. In order to achieve a good dissolution the active ingredient has to be sufficiently wetted.
The micronization of nebivolol hydrochloride as required in EP 0744946 B1 for preparing pharmaceutical compositions unjustifiably increases the time cycle for the manufacturing process. It also requires undue utilities like milling and sifting, which increases the cost of preparing the final product. It is further demonstrated that on comparison of dissolution of tablets comprising crystalline versus micronized nebivolol, the dissolution rate of the tablet comprising crystalline nebivolol (Example 6 of EP 744946) is less than 50% after 45 minutes.
EP 0145067 B1 provides pharmaceutical composition of derivatives of 2,2′-iminobisethanol for various dosage forms i.e. oral drops, injectable solution, oral solution, film coated tablets and the like. The use of sodium dodecyl sulfate is disclosed in EP 0145067 B1 in the preparation of film-coated tablet. Sodium dodecyl sulfate, i.e., sodium lauryl sulfate, (Wade, A. and Weller P. J., Handbook of Pharmaceutical Excipients, 2nd ed., 1994, page 448) is a wetting agent in the core of the composition (film coated tablet).
WO 2002/087508 discloses nitrosated and nitrosylated nebivolol and its metabolites and pharmaceutical composition using the same. It is disclosed that the bio-availability of the composition can be enhanced by micronization of the formulation using conventional techniques such as grinding, milling, spray drying and the like in the presence of suitable excipients or agents such as phospholipids or surfactants.
Thus, the existing literature reveals that attempts to use the natural crystalline form of nebivolol have resulted in poor dissolution rate and poor bioavailability. Attempts for combining the crystalline form with a wetting agent are also largely unsuccessful. For achieving appropriate dissolution rate or bioavailability of nebivolol hydrochloride, micronized nebivolol is needed. The micronization process is both cost extensive and time consuming, and requires the use of wetting agent.
Wetting agent is a surfactant, a substance capable of reducing the surface tension of a liquid in which it is dissolved. The effect of surfactant over the intestinal membrane is more complex. It has been shown that most surfactants interact with the absorbing membranes (Bermejo, D. M. and Ruiz-Garcia, A., Business Briefing: Pharmatech 2003; pages 1-7). Permeability enhancement and local damage are closely related sequelae of the interaction of surfactants with the intestinal wall (Swenson, E. S., Milisen, W. B., Curatolo, W., Pharm. Res. 1994 August; 11(8), pages 1132-42). Ingested surfactants may facilitate penetration or absorption of potentially toxic or pathogenic compounds, which in turn may result in adverse effects on the other organs (Lieberman, H. A., Rieger, M. M. and Banker, G. S., Eds., Pharmaceutical. Dosage Forms: Disperse Systems, 2nd ed, Vol. 1, page 261). The surfactant can facilitate their own entry and that of other material into the body, which thus enters in to the systemic circulation (Lieberman, H. A., Rieger, M. M. and Banker, G. S., Eds., Pharmaceutical Dosage Forms: Disperse Systems, 2nd ed., Vol. 1, page 264).
Polysorbate 60 or 80 affects the integrity of intestinal mucosa (Lieberman, H. A., Rieger, M. M. and Banker, G. S., Eds., Pharmaceutical Dosage Forms: Disperse Systems, 2nd ed., Vol. 1, page 261). Polysorbate 80 may increase the absorption of fat-soluble substances (www.lactose.co.uk/milkallergy/foodadditives400.html).
Management of hypertension being a long term therapy, use of wetting agents in the formulation of nebivolol need to be judiciously avoided. Large doses of polysorbate 80 as a wetting agent in pharmaceutical formulations produces abdominal spasms, diarrhea (http://www.jtbker.com/msds/englishhtml/t7683.htm). Further, polysorbate 80 containing pharmaceutical compositions have found to cause allergy in various patients (http://www.hci.utah.edu/patientdocs/hci/drugd/docetaxel.htm). Polysorbate 20 and polysorbate 40 should also be avoided in formulations as they are banned in certain countries (http://www.lactose.co.uk/milkallergy/foodadditives400.html).
Thus there is a long felt need to have compositions of nebivolol that are safe and efficacious at the same time being cost and time effective for manufacturing.
The present inventors have surprisingly found that pharmaceutical compositions of the present invention prepared using nebivolol as the active ingredient and without using wetting agent, exhibited excellent dissolution characteristics that were also found to be comparable with respect to the marketed formulation.
It was further surprisingly found that nebivolol hydrochloride could be formulated not only without the use of wetting agent but optionally without using binder or disintegrant without retarding the dissolution characteristics of the drug.